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Abstract Sacituzumab Govitecan (SG) is an antibody-drug conjugate that has demonstrated efficacy in patients with TROP-2 expressing epithelial cancers. In a xenograft model of intracranial breast cancer, SG inhibited tumor growth and increased mouse survival. We conducted a prospective window-of-opportunity trial (NCT03995706) at the University of Texas Health Science Center at San Antonio to examine the intra-tumoral concentrations and intracranial activity of SG in patients undergoing craniotomy for breast cancer with brain metastases (BCBM) or recurrent glioblastoma (rGBM). We enrolled 25 patients aged ≥18 years diagnosed with BCBM and rGBM to receive a single intravenous dose of SG at 10 mg/kg given one day before resection and continued on days 1 and 8 of 21-day cycles following recovery. The PFS was 8 months and 2 months for BCBM and rGBM cohorts, respectively. The OS was 35.2 months and 9.5 months, respectively. Grade≥3 AE included neutropenia (28%), hypokalemia (8%), seizure (8%), thromboembolic event (8%), urinary tract infection (8%) and muscle weakness of the lower limb (8%). In post-surgical tissue, the median total SN-38 was 249.8 ng/g for BCBM and 104.5 ng/g for rGBM, thus fulfilling the primary endpoint. Biomarker analysis suggests delivery of payload by direct release at target site and that hypoxic changes do not drive indirect release. Secondary endpoint of OS was 35.2 months for the BCBM cohort and 9.5 months for rGBM. Non-planned exploratory endpoint of ORR was 38% for BCBM and 29%, respectively. Exploratory endpoint of Trop-2 expression was observed in 100% of BCBM and 78% of rGBM tumors. In conclusion, SG was found to be well tolerated with adequate penetration into intracranial tumors and promising preliminary activity within the CNS. Trial Registration: Trial (NCT03995706) enrolled at Clinical Trials.gov as Neuro/Sacituzumab Govitecan/Breast Brain Metastasis/Glioblastoma/Ph 0: https://clinicaltrials.gov/study/NCT03995706?cond=NCT03995706 .

BACKGROUND:. Early diagnostic uncertainty for infection causes delays in antibiotic administration in infected patients and unnecessary antibiotic administration in noninfected patients. OBJECTIVE:. To develop a machine learning model for the early detection of untreated infection (eDENTIFI), with the presence of infection determined by clinician chart review. DERIVATION COHORT:. Three thousand three hundred fifty-seven adult patients hospitalized between 2006 and 2018 at two health systems in Illinois, United States. VALIDATION COHORT:. We validated in 1632 patients in a third Illinois health system using area under the receiver operating characteristic curve (AUC). PREDICTION MODEL:. Using a longitudinal discrete-time format, we trained a gradient boosted machine model to predict untreated infection in the next 6 hours using routinely available patient demographics, vital signs, and laboratory results. RESULTS:. eDENTIFI had an AUC of 0.80 (95% CI, 0.79–0.81) in the validation cohort and outperformed the systemic inflammatory response syndrome criteria with an AUC of 0.64 (95% CI, 0.64–0.65; p < 0.001). The most important features were body mass index, age, temperature, and heart rate. Using a threshold with a 47.6% sensitivity, eDENTIFI detected infection a median 2.0 hours (interquartile range, 0.9–5.2 hr) before antimicrobial administration, with a negative predictive value of 93.6%. Antibiotic administration guided by eDENTIFI could have decreased unnecessary IV antibiotic administration in noninfected patients by 10.8% absolute or 46.4% relative percentage points compared with clinicians. CONCLUSION:. eDENTIFI could both decrease the time to antimicrobial administration in infected patients and unnecessary antibiotic administration in noninfected patients. Further prospective validation is needed.

IMPORTANCE:. Timely intervention for clinically deteriorating ward patients requires that care teams accurately diagnose and treat their underlying medical conditions. However, the most common diagnoses leading to deterioration and the relevant therapies provided are poorly characterized. OBJECTIVES:. We aimed to determine the diagnoses responsible for clinical deterioration, the relevant diagnostic tests ordered, and the treatments administered among high-risk ward patients using manual chart review. DESIGN, SETTING, AND PARTICIPANTS:. This was a multicenter retrospective observational study in inpatient medical-surgical wards at four health systems from 2006 to 2020. Randomly selected patients (1000 from each health system) with clinical deterioration, defined by reaching the 95th percentile of a validated early warning score, electronic Cardiac Arrest Risk Triage, were included. MAIN OUTCOMES AND MEASURES:. Clinical deterioration was confirmed by a trained reviewer or marked as a false alarm if no deterioration occurred for each patient. For true deterioration events, the condition causing deterioration, relevant diagnostic tests ordered, and treatments provided were collected. RESULTS:. Of the 4000 included patients, 2484 (62%) had clinical deterioration confirmed by chart review. Sepsis was the most common cause of deterioration (41%; n = 1021), followed by arrhythmia (19%; n = 473), while liver failure had the highest in-hospital mortality (41%). The most common diagnostic tests ordered were complete blood counts (47% of events), followed by chest radiographs (42%) and cultures (40%), while the most common medication orders were antimicrobials (46%), followed by fluid boluses (34%) and antiarrhythmics (19%). CONCLUSIONS AND RELEVANCE:. We found that sepsis was the most common cause of deterioration, while liver failure had the highest mortality. Complete blood counts and chest radiographs were the most common diagnostic tests ordered, and antimicrobials and fluid boluses were the most common medication interventions. These results provide important insights for clinical decision-making at the bedside, training of rapid response teams, and the development of institutional treatment pathways for clinical deterioration.

Abstract Despite being mutated in 92% of TP53 mutant cancers, how mutations on p53 isoforms affect their activities remain largely unknown. Therefore, exploring the effect of mutations on p53 isoforms activities is a critical, albeit unexplored area in the p53 field. In this article, we report for the first time a mutant Δ133p53α-specific pathway which increases IL4I1 and IDO1 expression and activates AHR, a tumor-promoting mechanism. Accordingly, while WT Δ133p53α reduces apoptosis to promote DNA repair, mutant R273H also reduces apoptosis but fails to maintain genomic stability, increasing the risks of accumulation of mutations and tumor’s deriving towards a more aggressive phenotype. Furthermore, using 2D and 3D spheroids culture, we show that WT Δ133p53α reduces cell proliferation, EMT, and invasion, while the mutant Δ133p53α R273H enhances all three processes, confirming its oncogenic potential and strongly suggesting a similar in vivo activity. Importantly, the effects on cell growth and invasion are independent of mutant full-length p53α, indicating that these activities are actively carried by mutant Δ133p53α R273H. Furthermore, both WT and mutant Δ133p53α reduce cellular senescence in a senescence inducer-dependent manner (temozolomide or radiation) because they regulate different senescence-associated target genes. Hence, WT Δ133p53α rescues temozolomide-induced but not radiation-induced senescence, while mutant Δ133p53α R273H rescues radiation-induced but not temozolomide-induced senescence. Lastly, we determined that IL4I1, IDO1, and AHR are significantly higher in GBMs compared to low-grade gliomas. Importantly, high expression of all three genes in LGG and IL4I1 in GBM is significantly associated with poorer patients’ survival, confirming the clinical relevance of this pathway in glioblastomas. These data show that, compared to WT Δ133p53α, R273H mutation reorientates its activities toward carcinogenesis and activates the oncogenic IL4I1/IDO1/AHR pathway, a potential prognostic marker and therapeutic target in GBM by combining drugs specifically modulating Δ133p53α expression and IDO1/Il4I1/AHR inhibitors.

Abstract Central nervous system tumors have resisted effective chemotherapy because most therapeutics do not penetrate the blood-tumor-brain-barrier. Nanomedicines between ~ 10 and 100 nm accumulate in many solid tumors by the enhanced permeability and retention effect, but it is controversial whether the effect can be exploited for treatment of brain tumors. PLX038A is a long-acting prodrug of the topoisomerase 1 inhibitor SN-38. It is composed of a 15 nm 4-arm 40 kDa PEG tethered to four SN-38 moieties by linkers that slowly cleave to release the SN-38. The prodrug was remarkably effective at suppressing growth of intracranial breast cancer and glioblastoma (GBM), significantly increasing the life span of mice harboring them. We addressed the important issue of whether the prodrug releases SN-38 systemically and then penetrates the brain to exert anti-tumor effects, or whether it directly penetrates the blood-tumor-brain-barrier and releases the SN-38 cargo within the tumor. We argue that the amount of SN-38 formed systemically is insufficient to inhibit the tumors, and show by PET imaging that a close surrogate of the 40 kDa PEG carrier in PLX038A accumulates and is retained in the GBM. We conclude that the prodrug penetrates the blood-tumor-brain-barrier, accumulates in the tumor microenvironment and releases its SN-38 cargo from within. Based on our results, we pose the provocative question as to whether the 40 kDa nanomolecule PEG carrier might serve as a “Trojan horse” to carry other drugs past the blood-tumor-brain-barrier and release them into brain tumors.

Abstract Objective High self‐efficacy is associated with improved self‐care and reduced symptoms in cancer patients but has not been fully interrogated in adults with central nervous system (CNS) cancers. We aimed to identify the relationship between self‐efficacy levels in managing emotions (SEMEM) and social interactions (SEMSI) by examining sample characteristics and symptom burden. Methods Sample characteristics and patient‐reported outcome (PRO) measures addressing self‐efficacy (PROMIS SEMEM & SEMSI) and symptom burden (MDASI BT or SP) were collected in a novel web‐based study of 158 adult patients diagnosed with rare CNS tumors. Results The sample was predominantly female (73%), diagnosed with an ependymoma (66%), and had a median age of 45 (19–75). Low SEMEM was associated with a longer duration of symptoms before surgery (r = −0.26) and female gender (92%) among brain tumor (BT) participants and in spinal cord tumors (SCT), those with lower education (r = 0.29). Reporting low SEMSI was associated with being married (42%), lower education (r = 0.22), and a prolonged time with symptoms before surgery (r = 0.29) in those with BTs, with no associations identified in SCT. More severe mood‐related interference (including mood, enjoyment of life, and relationship with others) was associated with lower SEMEM among both locations (r = −0.61 brain, r = −0.28 spine) and SEMSI in BT participants (r = −0.54). Conclusions Low self‐efficacy was linked to a prolonged time between symptom onset and initial surgery, education, gender, and marital status and was associated with higher mood‐related interference. Understanding characteristics associated with low self‐efficacy underscores a need for future studies to tailor interventions that enhance self‐efficacy.

Abstract Despite strides in immunotherapy, glioblastoma multiforme (GBM) remains challenging due to low inherent immunogenicity and suppressive tumor microenvironment. Converting “cold” GBMs to “hot” is crucial for immune activation and improved outcomes. This study comprehensively characterized a therapeutic vaccination strategy for preclinical GBM models. The vaccine consists of Mannan‐BAM‐anchored irradiated whole tumor cells, Toll‐like receptor ligands [lipoteichoic acid (LTA), polyinosinic‐polycytidylic acid (Poly (I:C)), and resiquimod (R‐848)], and anti‐CD40 agonistic antibody (rWTC‐MBTA). Intracranial GBM models (GL261, SB28 cells) are used to evaluate the vaccine efficacy. A substantial number of vaccinated mice exhibited complete regression of GBM tumors in a T‐cell‐dependent manner, with no significant toxicity. Long‐term tumor‐specific immune memory is confirmed upon tumor rechallenge. In the vaccine‐draining lymph nodes of the SB28 model, rWTC‐MBTA vaccination triggered a major rise in conventional dendritic cell type 1 (cDC1) 12 h post‐treatment, followed by an increase in conventional dendritic cell type 2 (cDC2), monocyte‐derived dendritic cell (moDC), and plasmacytoid dendritic cell (pDC) on Day 5 and Day 13. Enhanced cytotoxicity of CD4+ and CD8+ T cells in vaccinated mice is verified in co‐culture with tumor cells. Analyses of immunosuppressive signals (T‐cell exhaustion, myeloid‐derived suppressor cells (MDSC), M2 macrophages) in the GBM microenvironment suggest potential combinations with other immunotherapies for enhanced efficacy. In conclusion, the authors findings demonstrate that rWTC‐MBTA induces potent and long‐term adaptive immune responses against GBM.

Abstract Background Clinical outcome assessments (COAs) are key to patient‐centered evaluation of novel interventions and supportive care. COAs are particularly informative in oncology where a focus on how patients feel and function is paramount, but their incorporation in trial outcomes have lagged that of traditional survival and tumor responses. To understand the trends of COA use in oncology and the impact of landmark efforts to promote COA use, we computationally surveyed oncology clinical trials in ClinicalTrials.gov comparing them to the rest of the clinical research landscape. Methods Oncology trials were identified using medical subject heading neoplasm terms. Trials were searched for COA instrument names obtained from PROQOLID. Regression analyses assessed chronological and design‐related trends. Results Eighteen percent of oncology interventional trials initiated 1985–2020 (N = 35,415) reported using one or more of 655 COA instruments. Eighty‐four percent of the COA‐using trials utilized patient‐reported outcomes, with other COA categories used in 4–27% of these trials. Likelihood of COA use increased with progressing trial phase (OR = 1.30, p

IntroductionCritical deterioration in hospitalized children, defined as ward to pediatric intensive care unit (PICU) transfer followed by mechanical ventilation (MV) or vasoactive infusion (VI) within 12 h, has been used as a primary metric to evaluate the effectiveness of clinical interventions or quality improvement initiatives. We explore the association between critical events (CEs), i.e., MV or VI events, within the first 48 h of PICU transfer from the ward or emergency department (ED) and in-hospital mortality.MethodsWe conducted a retrospective study of a cohort of PICU transfers from the ward or the ED at two tertiary-care academic hospitals. We determined the association between mortality and occurrence of CEs within 48 h of PICU transfer after adjusting for age, gender, hospital, and prior comorbidities.ResultsExperiencing a CE within 48 h of PICU transfer was associated with an increased risk of mortality [OR 12.40 (95% CI: 8.12–19.23, P

Abstract Background Primary brain tumor (PBT) patients experience higher levels of distress and anxiety than other solid tumor patients, particularly at the time of clinical evaluation when uncertainty about disease status is high (“scanxiety”). There is promising evidence supporting use of virtual reality (VR) to target psychological symptoms in other solid tumor patients, though PBT patients have not been studied extensively in this context. The primary aim of this phase 2 clinical trial is to establish the feasibility of a remote VR-based relaxation intervention for a PBT population, with secondary aims designed to determine preliminary efficacy of improving distress and anxiety symptoms. Methods PBT patients (N = 120) with upcoming MRI scans and clinical appointments who meet eligibility will be recruited to participate in a single arm trial conducted remotely through the NIH. Following completion of baseline assessments, participants will complete a 5-min VR intervention via telehealth using a head-mounted immersive device while under supervision of the research team. Following the intervention, over the course of 1 month patients can use VR at their discretion with follow-up assessments done immediately post-VR intervention, as well as 1 week and 4 weeks later. Additionally, a qualitative phone interview will be conducted to assess patient satisfaction with the intervention. Discussion Use of immersive VR is an innovative interventional approach to target distress and scanxiety symptoms in PBT patients who are at high risk for experiencing these symptoms leading into their clinical appointments. Findings from this study may inform design of a future multicenter randomized VR trial for PBT patients and may aid in development of similar interventions for other oncology populations. Trial Registration Clinicaltrials.gov (NCT04301089), registered 9 March 2020.

Abstract Cancer cell metabolism is often deregulated as a result of adaption to meeting energy and biosynthesis demands of rapid growth or direct mutation of key metabolic enzymes. Better understanding of such deregulation can provide new insights on targetable vulnerabilities, but is complicated by the difficulty in probing cell metabolism at different levels of resolution and under different experimental conditions. We construct computational models of glucose and glutamine metabolism with focus on the effect of IDH1/2-mutations in cancer using a combination of experimental metabolic flux data and patient-derived gene expression data. Our models demonstrate the potential of computational exploration to reveal biologic behavior: they show that an exogenously-mutated IDH1 experimental model utilizes glutamine as an alternative carbon source for lactate production under hypoxia, but does not fully-recapitulate the patient phenotype under normoxia. We also demonstrate the utility of using gene expression data as a proxy for relative differences in metabolic activity. We use the approach of probabilistic model checking and the freely-available Probabilistic Symbolic Model Checker to construct and reason about model behavior.

Introduction: Ensuring that people at risk of overdosing on opioids have easy access to naloxone is an essential part of the fight against the opioid crisis. This study evaluates the impact of the 2016 California law (CA AB1535) permitting pharmacies to dispense this life-saving medication without a physician's prescription. Methods: California counties were categorized on the basis of population density (rural, suburban, urban), rate of opioid-related deaths by population density (high, medium, low), and rate of opioid prescriptions by population density (high, medium, low). Ten diverse pharmacies from each category were selected for inclusion. In a brief 1-minute interview conducted between July and August 2021, pharmacists from 146 California pharmacies were surveyed regarding their knowledge of CA AB1535, their practice of dispensing naloxone without a physician's prescription, and whether they normally stock naloxone. Chi-square tests were used to compare responses. Results: Although almost all pharmacies interviewed (94%) were aware of the law and most of them (64%) dispensed naloxone without a physician's prescription, few statistically significant differences were found between surveyed categories. There were no significant relationships between naloxone availability at pharmacies and overdose death rates. Conclusions: Our results suggest that the number of California pharmacies dispensing naloxone without a physician's prescription has continued to increase since the implementation of CA AB1535. However, despite increased access to naloxone at pharmacies, opioid overdose rates have continued to rise since 2016, indicating the need for a multifaceted harm reduction approach.

Computational models of cells cannot be considered complete unless they include the most fundamental process of life, the replication and inheritance of genetic material. By creating a computational framework to model systems of replicating bacterial chromosomes as polymers at 10 bp resolution with Brownian dynamics, we investigate changes in chromosome organization during replication and extend the applicability of an existing whole-cell model (WCM) for a genetically minimal bacterium, JCVI-syn3A, to the entire cell-cycle. To achieve cell-scale chromosome structures that are realistic, we model the chromosome as a self-avoiding homopolymer with bending and torsional stiffnesses that capture the essential mechanical properties of dsDNA in Syn3A. In addition, the conformations of the circular DNA must avoid overlapping with ribosomes identitied in cryo-electron tomograms. While Syn3A lacks the complex regulatory systems known to orchestrate chromosome segregation in other bacteria, its minimized genome retains essential loop-extruding structural maintenance of chromosomes (SMC) protein complexes (SMC-scpAB) and topoisomerases. Through implementing the effects of these proteins in our simulations of replicating chromosomes, we find that they alone are sufficient for simultaneous chromosome segregation across all generations within nested theta structures. This supports previous studies suggesting loop-extrusion serves as a near-universal mechanism for chromosome organization within bacterial and eukaryotic cells. Furthermore, we analyze ribosome diffusion under the influence of the chromosome and calculate in silico chromosome contact maps that capture inter-daughter interactions. Finally, we present a methodology to map the polymer model of the chromosome to a Martini coarse-grained representation to prepare molecular dynamics models of entire Syn3A cells, which serves as an ultimate means of validation for cell states predicted by the WCM.

This article is a theological analysis of African American preaching as a genre of Christian discourse. After first recognizing the particular influences of African culture, American slavery, other religious traditions, and the role its practitioners have played in defining its traditions and cultural form as sacred speech, this article explores its nature, function, and scope, and gives a brief genealogical account of African American preaching in North America. Following this historical treatment, this article discusses contrastive hermeneutical perspectives on biblical interpretation, theological emphases (e.g. God, salvation, eschatology, suffering, human freedom, etc.) privileged by its practitioners, and then details rhetorical approaches germane to its communal influence, social relevance, and theological shaping within contexts of Black religious life and beyond. As a theo-rhetorical discourse esteemed for its persistent calls for justice, ecclesiastical reform, spiritual redemption, and moral and ethical responsibility, this article will also consider contemporary trends, theories, and innovations on the horizon in African American homiletic theory and practice.

Human endogenous retroviruses (HERVs) are ancestral viral relics that constitute nearly 8% of the human genome. Although normally silenced, the most recently integrated provirus HERV-K (HML-2) can be reactivated in certain cancers. Here, we report pathological expression of HML-2 in malignant gliomas in both cerebrospinal fluid and tumor tissue that was associated with a cancer stem cell phenotype and poor outcomes. Using single-cell RNA-Seq, we identified glioblastoma cellular populations with elevated HML-2 transcripts in neural progenitor–like cells (NPC-like) that drive cellular plasticity. Using CRISPR interference, we demonstrate that HML-2 critically maintained glioblastoma stemness and tumorigenesis in both glioblastoma neurospheres and intracranial orthotopic murine models. Additionally, we demonstrate that HML-2 critically regulated embryonic stem cell programs in NPC-derived astroglia and altered their 3D cellular morphology by activating the nuclear transcription factor OCT4, which binds to an HML-2–specific long-terminal repeat (LTR5Hs). Moreover, we discovered that some glioblastoma cells formed immature retroviral virions, and inhibiting HML-2 expression with antiretroviral drugs reduced reverse transcriptase activity in the extracellular compartment, tumor viability, and pluripotency. Our results suggest that HML-2 fundamentally contributes to the glioblastoma stem cell niche. Because persistence of glioblastoma stem cells is considered responsible for treatment resistance and recurrence, HML-2 may serve as a unique therapeutic target.

Abstract Disrupted sleep, including daytime hypersomnolence, is a core symptom reported by primary brain tumor patients and often manifests after radiotherapy. The biological mechanisms driving the onset of sleep disturbances after cranial radiation remains unclear but may result from treatment-induced injury to neural circuits controlling sleep behavior, both circadian and homeostatic. Here, we develop a mouse model of cranial radiation-induced hypersomnolence which recapitulates the human experience. Additionally, we used the model to explore the impact of radiation on the brain. We demonstrated that the DNA damage response following radiation varies across the brain, with homeostatic sleep and cognitive regions expressing higher levels of γH2AX, a marker of DNA damage, than the circadian suprachiasmatic nucleus (SCN). These findings were supported by in vitro studies comparing radiation effects in SCN and cortical astrocytes. Moreover, in our mouse model, MRI identified structural effects in cognitive and homeostatic sleep regions two-months post-treatment. While the findings are preliminary, they suggest that homeostatic sleep and cognitive circuits are vulnerable to radiation and these findings may be relevant to optimizing treatment plans for patients.

Spinodal phase separation in SMART (Self-passivating Metal Alloys with Reduced Thermo-oxidation) materials based on binary W-Cr with alloying elements Y and Zr is systematically investigated by a combination of Density Functional Theory with Cluster Expansion Hamiltonian and large-scale Monte Carlo simulations with thermodynamic integration. Comparing alloys of Zr with those of Y in ternary compositions with W and Cr, it is shown that there is a significant difference in the average short-range order between W and Zr, which changes from positive to negative from 500 K to higher temperatures in W70Cr29Zr1 alloys compared with the positive SRO (Short-Range Order) between W and Y in W70Cr29Y1 alloys at all temperatures. This change, however, does not affect the segregation behavior between W and Cr in the whole range of temperature between these alloys. Importantly, it is found that co-segregation of Y and Zr due to the negative SRO between them, in W70Cr29Y0.5Zr0.5 and W70Cr28Y1Zr1 considered alloys, increases the W-Cr positive SRO closer to the binary W70Cr30. Our modeling results reveal a significant impact on spinodal phase segregation of W and Cr in designing SMART materials for DEMO devices of future fusion power plants. Findings from recent experimental studies validate the modeling results, particularly the high-temperature behavior of the W-Cr-Zr alloys and the microstructure evolution of the W-Cr-Y-Zr alloys. The results provide a fundamental understanding of the radiation resistance phenomena observed in recent experiments on neutron-irradiated self-passivating alloys.

In embryonal rhabdomyosarcoma (ERMS) and generally in sarcomas, the role of wild-type and loss- or gain-of-function TP53 mutations remains largely undefined. Eliminating mutant or restoring wild-type p53 is challenging; nevertheless, understanding p53 variant effects on tumorigenesis remains central to realizing better treatment outcomes. In ERMS, >70% of patients retain wild-type TP53, yet mutations when present are associated with worse prognosis. Employing a kRASG12D-driven ERMS tumor model and tp53 null (tp53-/-) zebrafish, we define wild-type and patient-specific TP53 mutant effects on tumorigenesis. We demonstrate that tp53 is a major suppressor of tumorigenesis, where tp53 loss expands tumor initiation from 97% of animals. Characterizing three patient-specific alleles reveals that TP53C176F partially retains wild-type p53 apoptotic activity that can be exploited, whereas TP53P153Δ and TP53Y220C encode two structurally related proteins with gain-of-function effects that predispose to head musculature ERMS. TP53P153Δ unexpectedly also predisposes to hedgehog-expressing medulloblastomas in the kRASG12D-driven ERMS-model.

Nutritional intervention is becoming more prevalent as adjuvant therapy for many cancers in view of the tumor dependence on external sources for some nutrients. However, little is known about the mechanisms that make cancer cells require certain nutrients from the microenvironment. Herein, we report the dependence of glioma cells on exogenous cysteine/cystine, despite this amino acid being nonessential. Using several 13C‐tracers and analysis of cystathionine synthase and cystathioninase levels, we revealed that glioma cells were not able to support glutathione synthesis through the transsulfuration pathway, which allows methionine to be converted to cysteine in cysteine/cystine‐deprived conditions. Therefore, we explored the nutritional deprivation in a mouse model of glioma. Animals subjected to a cysteine/cystine‐free diet survived longer, although this increase did not attain statistical significance, with concomitant reductions in plasma glutathione and cysteine levels. At the end point, however, tumors displayed the ability to synthesize glutathione, even though higher levels of oxidative stress were detected. We observed a compensation from the nutritional intervention revealed as the recovery of cysteine‐related metabolite levels in plasma. Our study highlights a time window where cysteine deprivation can be exploited for additional therapeutic strategies.

Background: Tendon-to-bone (TtB) healing is essential for successful rotator cuff repair (RCR). This study aimed to investigate if caffeine intake impaired TtB healing in a rat RCR model. Methods: Seventy-two rats were randomized into a caffeinated group or a noncaffeinated group. Specimens received one week of oral caffeine solution or normal saline before RCR. All rats then underwent bilateral RCR. Caffeination or saline gavages continued until rats were sacrificed at 2, 4, and 8 weeks postoperatively. Load-to-failure (primary outcomes measure), maximum stress, and stiffness of the TtB interface were measured for one shoulder of each specimen. Six random shoulders from each group underwent histological assessment of TtB healing. Results: Load-to-failure and maximum stress of RCR did not appear to differ between groups at any time point. No difference in RCR stiffness was found between groups at 2 and 4 weeks; however, stiffness in the caffeinated group did appear to lower at 8 weeks (P = .04). Conclusion: Perioperative caffeine intake did not appear to affect load-to-failure strength of RCR in an animal model. Although our secondary outcome measures of maximum stress and stiffness also did not appear to be influenced by perioperative caffeine intake, there did appear to be a trend toward decreased RCR stiffness at 8 weeks postoperatively in specimens that received caffeine.

Abstract Comprising approximately 8% of our genome, Human Endogenous RetroViruses (HERVs) represent a class of germline retroviral infections that are regulated through epigenetic modifications. In cancer cells, which often have epigenetic dysregulation, HERVs have been implicated as potential oncogenic drivers. However, their role in gliomas is not known. Given the link between HERV expression in cancer cell lines and the distinct epigenetic dysregulation in gliomas, we utilized a tailored bioinformatic pipeline to characterize and validate the glioma retrotranscriptome and correlate HERV expression with locus-specific epigenetic modifications. We identified robust overexpression of multiple HERVs in our cell lines, including a retroviral transcript, HML-6, at 19q13.43b in glioblastoma cells. HERV expression inversely correlated with loci-specific DNA methylation. HML-6 contains an intact open reading frame encoding a small envelope protein, ERVK3-1. Increased expression of ERVK3-1 in GBM patients is associated with a poor prognosis independent of IDH-mutational status. Our results suggest that not only is HML-6 uniquely overexpressed in highly invasive cell lines and tissue samples, but also its gene product, ERVK3-1, may be associated with reduced survival in GBM patients. These results may have implications for both the tumor biology of GBM and the role of ERVK3-1 as a potential therapeutic target.

Abstract Background Compared to normal cells, cancer cells exhibit a higher level of oxidative stress, which primes key cellular and metabolic pathways and thereby increases their resilience under oxidative stress. This higher level of oxidative stress also can be exploited to kill tumor cells while leaving normal cells intact. In this study we have found that isovalerylspiramycin I (ISP I), a novel macrolide antibiotic, suppresses cancer cell growth and tumor metastases by targeting the nucleolar protein selenoprotein H (SELH), which plays critical roles in keeping redox homeostasis and genome stability in cancer cells. Methods We developed ISP I through genetic recombination and tested the antitumor effects using primary and metastatic cancer models. The drug target was identified using the drug affinity responsive target stability (DARTS) and mass spectrum assays. The effects of ISP I were assessed for reactive oxygen species (ROS) generation, DNA damage, R-loop formation and its impact on the JNK2/TIF-IA/RNA polymerase I (POLI) transcription pathway. Results ISP I suppresses cancer cell growth and tumor metastases by targeting SELH. Suppression of SELH induces accumulation of ROS and cancer cell-specific genomic instability. The accumulation of ROS in the nucleolus triggers nucleolar stress and blocks ribosomal RNA transcription via the JNK2/TIF-IA/POLI pathway, causing cell cycle arrest and apoptosis in cancer cells. Conclusions We demonstrated that ISP I links cancer cell vulnerability to oxidative stress and RNA biogenesis by targeting SELH. This suggests a potential new cancer treatment paradigm, in which the primary therapeutic agent has minimal side-effects and hence may be useful for long-term cancer chemoprevention.

Introduction. Proximal tibia physeal fractures in children are not very common but can be dangerous because they can harm popliteal fossa structures, especially the popliteal artery. Popliteal artery injuries (PAI) are most commonly the result of trauma to the lower extremity, including blunt force, hyperextension injuries, complex fractures, and knee dislocations that can compromise popliteal neurovascular structures. Case Presentation. A 14-year-old boy presents to the emergency department after being transferred from an outside hospital 24 hours after a left lower extremity hyperextension injury. Radiographs demonstrated a Salter-Harris III proximal tibia fracture with posterior displacement. ABIs were deferred due to palpable distal pulses and no evidence of compartment syndrome. Closed reduction and percutaneous pinning were planned to correct the fracture. Intraoperatively, it was discovered that knee extension decreased lower extremity perfusion while knee flexion returned perfusion. An angiography revealed a popliteal artery occlusion with no distal flow. Based on this, an above-knee to below-knee popliteal bypass using the contralateral great saphenous vein was performed followed by closed reduction and percutaneous pinning of the proximal tibia. Conclusion. Proximal tibia physeal injuries, especially the Salter-Harris III and IV injuries, warrant a high index of suspicion of popliteal artery injuries. Palpable pulses and delayed presentation in the distal lower extremity do not rule out a PAI because collateral flow to the anterior and posterior tibial arteries may mask signs of an avascular limb, highlighting the need for a thorough history and physical exam. The authors present this case to reaffirm the importance of an ankle-brachial index when evaluating hyperextension injuries with proximal tibial epiphyseal fractures.

The uncommon MN1-altered primary central nervous system (CNS) tumors were recently added to the World Health Organization 2021 classification under the name Astroblastoma, MN1-altered. Another term used to describe them, “High-grade neuroepithelial tumor with MN1 alteration” (HGNET-MN1), makes reference to their distinct epigenetic profile but is currently not a recommended name. Thought to occur most commonly in children and predominantly in females, MN1-altered CNS tumors are associated with typical but not pathognomonic histological patterns and are characterized by a distinct DNA methylation profile and recurrent fusions implicating the MN1 (meningioma 1) gene. Diagnosis based on histological features alone is challenging: most cases with morphological features of astroblastoma (but not all) show these molecular features, whereas not all tumors with MN1 fusions show astroblastoma morphology. There is large variability in reported outcomes and detailed clinical and therapeutic information is frequently missing. Some patients experience multiple recurrences despite multimodality treatment, whereas others experience no recurrence after surgical resection alone, suggesting large clinical and biological heterogeneity despite unifying epigenetic features and recurrent fusions. In this report, we present the demographics, tumor characteristics, treatment, and outcome (including patient-reported outcomes) of three adults with MN1-altered primary CNS tumors diagnosed via genome-wide DNA methylation and RNA sequencing. All three patients were females and two of them were diagnosed as young adults. By reporting our neuropathological and clinical findings and comparing them with previously published cases we provide insight into the clinical heterogeneity of this tumor. Additionally, we propose a model for prospective, comprehensive, and systematic collection of clinical data in addition to neuropathological data, including standardized patient-reported outcomes.

The ultimate microscope, directed at a cell, would reveal the dynamics of all the cell’s components with atomic resolution. In contrast to their real-world counterparts, computational microscopes are currently on the brink of meeting this challenge. In this perspective, we show how an integrative approach can be employed to model an entire cell, the minimal cell, JCVI-syn3A, at full complexity. This step opens the way to interrogate the cell’s spatio-temporal evolution with molecular dynamics simulations, an approach that can be extended to other cell types in the near future.

Summary: Background: Recognising the importance of clinical outcomes assessments (COAs), the Response Assessment in Neuro-Oncology-Patient Reported Outcome (RANO-PRO) Working Group recommended inclusion of core symptoms and functions in clinical care or research for malignant glioma patients. This study evaluated the association of the recommended symptoms (pain, perceived cognition, seizures, aphasia, symptomatic adverse events) and functions (weakness, walking, work, usual activities) with disease progression in these patients. Methods: In this retrospective cohort study, patients with malignant glioma were included from the US National Cancer Institute Neuro-Oncology Branch Natural History Study (NOB–NHS) which follows primary central nervous system tumour patients aged 18 years and older throughout their disease trajectory. The M.D. Anderson Symptom Inventory-Brain Tumor (MDASI-BT), EQ-5D-3L, Karnofsky Performance Status (KPS), and Neurologic Function scores (NFS) were evaluated in relation to disease progression by chi-square tests, independent- and paired-samples t-tests, adjusted for multiple comparisons at first assessment and over time to a second assessment. Radiographic disease progression was determined on the interpretation of the imaging study by a radiologist and neuro-oncologist using standard criteria as part of clinical trial participation or routine standard of care. The priority constructs were evaluated to provide initial evidence of their relevance, relationship to disease status over time, and sensitivity to change in a diverse group of patients with malignant glioma. Findings: Seven hundred and sixty-five patients had enrolled into the NOB–NHS between September 1, 2016 and January 31, 2020. Three hundred and thirty-six patients had a diagnosis of a malignant glioma (anaplastic astrocytoma, anaplastic oligodendroglioma, glioblastoma, and gliosarcoma) and were included in the current study. The sample was 64% male (n = 215), 36% female (n = 121), median age of 52 years (IQR = 18.75), 82% White (n = 276), and 65% had tumour recurrence (n = 219). One hundred and fifty-four (46%) had radiographic disease progression. Difficulty remembering, fatigue, and weakness were worse in the group whose imaging was interpreted as radiographic disease progression versus stable disease, as well as the functions of walking, work, activity, and self-care (1.1 < difference < 1.8). Patients with disease progression were four times more likely to have a poor KPS (≤80) and worse NFS. Among patients with disease progression at a second assessment (n = 112), all symptoms, except seizures, worsened between first assessment and disease progression and up to 22% of patients (n = 25) reported worsening mobility, self-care, and usual activity; 46% (n = 51) and 35% (n = 30) had worsened KPS and NFS, respectively. On average, 4 symptoms or functions (SD = 3) were reported as moderate-to-severe and 30% (n = 33) and 23% (n = 26) had a change to moderate-to-severe fatigue and walking, respectively, at time of disease progression. Over 7% of patients with worsening (n = 7 of 100) reported every symptom and function as having changed the most severely including seizures with fatigue and activity reported as the top symptom and function, respectively. Interpretation: The identified core symptoms and functions worsened at the time of progression, supporting the relevance and sensitivity of the priority constructs identified by the RANO-PRO Working Group for clinical care and clinical trials for malignant glioma patients. Funding: The Natural History Study is supported by Intramural Project 1ZIABC011786-03.

Objectives: This study seeks to examine the provider and organizational factors that could be limiting the treatment of Opioid Use Disorder (OUD) for Black Americans in Texas. Formative research at the provider and organizational level will assist in understanding the current facilitators, potential barriers, and capacity for OUD treatment for Black Americans. Study design: Using the exploration phase of the Explore, Preparation, Implementation, Sustainment (EPIS) framework, the project will be a formative assessment of local factors that influence Medication for OUD (MOUD) treatment availability for Black Americans to guide the design of a culturally and locally relevant multi-level intervention strategy. Methods: and analysis: This project will utilize emergent mixed methods to identify and clarify the problems that are obstructing treatment for Black patients with OUD. First, the perspectives of individual providers in their openness and willingness to provide MOUD treatment to Black Americans diagnosed with OUD will be explored through in-depth interviews. The organizational capacity factors associated with increased availability to treatment for Black American OUD patients will be examined with the organizational leaders using an exploratory sequential mixed-methods design. Leader and program managers of organizations that provide MOUD will be invited to participate in an online survey, with the option to participate in a follow-up in-depth interview. All qualitative data from the provider and organization staff interviews will be analyzed with a thematic analysis approach. The analysis of the two different types of qualitative data will be analyzed together, as a form of triangulation. Conclusions: This project will assess the understandings of individual providers as well as the organizational-level awareness of the cultural contexts of MOUD intervention for Black Americans. This formative research seeks to highlight the current status of the opioid crisis in the Black community, and what additional supports are needed.

Astrocytomas are the most common subtype of brain tumors and no curative treatment exist. Longitudinal assessment of patients, usually via Magnetic Resonance Imaging (MRI), is crucial since tumor progression may occur earlier than clinical progression. MRI usually provides a means for monitoring the disease, but it only informs about the structural changes of the tumor, while molecular changes can occur as a treatment response without any MRI-visible change. Radiotherapy (RT) is routinely performed following surgery as part of the standard of care in astrocytomas, that can also include chemotherapy involving temozolomide. Monitoring the response to RT is a key factor for the management of patients. Herein, we provide plasma and tissue metabolic biomarkers of treatment response in a mouse model of astrocytoma that was subjected to radiotherapy. Plasma metabolic profiles acquired over time by Liquid Chromatography Mass Spectrometry (LC/MS) were subjected to multivariate empirical Bayes time-series analysis (MEBA) and Receiver Operating Characteristic (ROC) assessment including Random Forest as the classification strategy. These analyses revealed a variation of the plasma metabolome in those mice that underwent radiotherapy compared to controls; specifically, fumarate was the best discriminatory feature. Additionally, Nuclear Magnetic Resonance (NMR)-based 13C-tracing experiments were performed at end-point utilizing [U-13C]-Glutamine to investigate its fate in the tumor and contralateral tissues. Irradiated mice displayed lower levels of glycolytic metabolites (e.g. phosphoenolpyruvate) in tumor tissue, and a higher flux of glutamine towards succinate was observed in the radiation cohort. The plasma biomarkers provided herein could be validated in the clinic, thereby improving the assessment of brain tumor patients throughout radiotherapy. Moreover, the metabolic rewiring associated to radiotherapy in tumor tissue could lead to potential metabolic imaging approaches for monitoring treatment using blood draws.

Abstract Background To describe a case of pediatric sarcoidosis which initially presented as papillary conjunctivitis before manifesting as bilateral lacrimal gland swelling without other known systemic involvement. Case presentation A 10-year-old female presented to the pediatric ophthalmology clinic with complaints of bilateral eyelid swelling, tearing and itching for approximately 1 month. Her history and exam were most consistent with allergic conjunctivitis, for which she was started on a standard topical regimen. Despite initial improvement, she re-presented with significantly worsened eyelid swelling and minimal allergic symptoms. Enlargement of the lacrimal glands were palpable at this time. Lacrimal gland biopsy was obtained which demonstrated noncaseating granulomas. Systemic workup did not reveal evidence of disease involvement elsewhere. Conclusions Sarcoidosis in the pediatric population may present in a myriad of ways and is well-known to mimic other disease entities. We present a case of pediatric sarcoidosis which presented initially as papillary conjunctivitis before manifesting as bilateral lacrimal gland swelling without systemic involvement.

Most tumors, including brain tumors, are sporadic. However, a small subset of CNS tumors are associated with hereditary cancer conditions like Lynch Syndrome (LS). Here, we present a case of an oligodendroglioma, IDH-mutant and 1p/19q-codeleted, and LS with a germline pathogenic PMS2 mutation. To our knowledge, this has only been reported in a few cases in the literature. While the family history is less typical of LS, previous studies have indicated the absence of a significant family history in patient cohorts with PMS2 mutations due to its low penetrance. Notably, only a handful of studies have worked on characterizing PMS2 mutations in LS, and even fewer have looked at these mutations in the context of brain tumor development. This report aims to add to the limited literature on germline PMS2 mutations and oligodendrogliomas. It highlights the importance of genetic testing in neuro-oncology.

Cancer stem cells are thought to be the main drivers of tumorigenesis for malignancies such as glioblastoma (GBM). They are maintained through a close relationship with the tumor vasculature. Previous literature has well-characterized the components and signaling pathways for maintenance of this stem cell niche, but details on how the niche initially forms are limited. This review discusses development of the nonmalignant neural and hematopoietic stem cell niches in order to draw important parallels to the malignant environment. We then discuss what is known about the cancer stem cell niche, its relationship with angiogenesis, and provide a hypothesis for its development in GBM. A better understanding of the mechanisms of development of the tumor stem cell niche may provide new insights to potentially therapeutically exploit.

Abstract The glutamatergic modulator ketamine has been shown to rapidly reduce depressive symptoms in patients with treatment-resistant major depressive disorder (TRD). Although its mechanisms of action are not fully understood, changes in cortical excitation/inhibition (E/I) following ketamine administration are well documented in animal models and could represent a potential biomarker of treatment response. Here, we analyse neuromagnetic virtual electrode time series collected from the primary somatosensory cortex in 18 unmedicated patients with TRD and in an equal number of age-matched healthy controls during a somatosensory ‘airpuff’ stimulation task. These two groups were scanned as part of a clinical trial of ketamine efficacy under three conditions: (a) baseline; (b) 6–9 h following subanesthetic ketamine infusion; and (c) 6–9 h following placebo-saline infusion. We obtained estimates of E/I interaction strengths by using dynamic causal modelling (DCM) on the time series, thereby allowing us to pinpoint, under each scanning condition, where each subject’s dynamics lie within the Poincaré diagram—as defined in dynamical systems theory. We demonstrate that the Poincaré diagram offers classification capability for TRD patients, in that the further the patients’ coordinates were shifted (by virtue of ketamine) toward the stable (top-left) quadrant of the Poincaré diagram, the more their depressive symptoms improved. The same relationship was not observed by virtue of a placebo effect—thereby verifying the drug-specific nature of the results. We show that the shift in neural dynamics required for symptom improvement necessitates an increase in both excitatory and inhibitory coupling. We present accompanying MATLAB code made available in a public repository, thereby allowing for future studies to assess individually tailored treatments of TRD.

Abstract Age plays a critical role in disease development and tolerance to cancer treatment, often leading to an increased risk of developing negative symptoms including sleep disturbances. Circadian rhythms and sleep become disrupted as organisms age. In this study, we explored the behavioral alterations in sleep, circadian rhythms, and masking using a novel video system and interrogate the long-term impact of age-based changes in the non-image forming visual pathway on brain anatomy. We demonstrated the feasibility and utility of the novel system and establish that older mice have disruptions in sleep, circadian rhythms, and masking behaviors that were associated with major negative volume alterations in the non-imaging forming visual system, critical for the induction and rhythmic expression of sleep. These results provide important insights into a mechanism, showing brain atrophy is linked to age in distinct non-image forming visual regions, which may predispose older individuals to developing circadian and sleep dysfunction when further challenged by disease or treatment.

Abstract Background Complex pleural space infections are commonly managed with antibiotics, pleural drainage, intrapleural fibrinolytic therapy, and surgery. These strategies often utilize radiographic imaging during management, however little data is available on cumulative radiation exposure received during inpatient management. We aimed to identify the type and quantity of radiographic studies along with the resultant radiation exposure during the management of complex pleural space infections. Methods Retrospective review of community network healthcare system from January 2015 to July 2018. Patients were identified through billing databases as receiving intrapleural fibrinolytic therapy and/or surgical intervention. Patient demographics, clinical outcomes, and inpatient radiographic imaging was collected to calculate cumulative effective dose. Results A total of 566 patients were identified with 7275 total radiographic studies performed and a median cumulative effective dose of 16.9 (IQR 9.9–26.3) mSv. Multivariable linear regression analysis revealed computed tomography use was associated with increased cumulative dose, whereas increased age was associated with lower cumulative dose. Over 74% of patients received more than 10 mSv, with 7.4% receiving more than 40 mSv. Conclusions The number of radiographic studies and overall cumulative effective dose in patients hospitalized for complex pleural space infection was high with the median cumulative effective dose > 5 times normal yearly exposure. Ionizing radiation and modern radiology techniques have revolutionized medical care, but are likely not without risk. Additional study is warranted to identify the frequency and imaging type needed during complex pleural space infection management, attempting to keep ionizing radiation exposure as low as reasonably possible.

The effects of neutron irradiation on materials are often interpreted in terms of atomic recoils, initiated by neutron impacts and producing crystal lattice defects. In addition, there is a remarkable two-step process, strongly pronounced in the medium-weight and heavy elements. This process involves the generation of energetic γ photons in nonelastic collisions of neutrons with atomic nuclei, achieved via capture and inelastic reactions. Subsequently, high-energy electrons are excited through the scattering of γ photons by the atomic electrons. We derive and validate equations enabling a fast and robust evaluation of photon and electron fluxes produced by the neutrons in the bulk of materials. The two-step n-γ-e scattering creates a nonequilibrium dynamically fluctuating steady-state population of high-energy electrons, with the spectra of photon and electron energies extending well into the mega-electron-volt range. This stimulates vacancy diffusion through electron-triggered atomic recoils, primarily involving vacancy-impurity dissociation, even if thermal activation is ineffective. Tungsten converts the energy of fusion or fission neutrons into a flux of γ radiation at the conversion efficiency approaching 99%, with implications for structural materials, superconductors, and insulators, as well as phenomena like corrosion, and helium and hydrogen isotope retention.

Abstract Background It has been proposed that recently duplicated genes are more likely to be redundant with one another compared to ancient paralogues. The evolutionary logic underpinning this idea is simple, as the assumption is that recently derived paralogous genes are more similar in sequence compared to members of ancient gene families. We set out to test this idea by using molecular phylogenetics and exploiting the genetic tractability of the model nematode, Caenorhabditis elegans, in studying the nematode-specific family of Hedgehog-related genes, the Warthogs. Hedgehog is one of a handful of signal transduction pathways that underpins the development of bilaterian animals. While having lost a bona fide Hedgehog gene, most nematodes have evolved an expanded repertoire of Hedgehog-related genes, ten of which reside within the Warthog family. Results We have characterised their evolutionary origin and their roles in C. elegans and found that these genes have adopted new functions in aspects of post-embryonic development, including left–right asymmetry and cell fate determination, akin to the functions of their vertebrate counterparts. Analysis of various double and triple mutants of the Warthog family reveals that more recently derived paralogues are not redundant with one another, while a pair of divergent Warthogs do display redundancy with respect to their function in cuticle biosynthesis. Conclusions We have shown that newer members of taxon-restricted gene families are not always functionally redundant despite their recent inception, whereas much older paralogues can be, which is considered paradoxical according to the current framework in gene evolution.

The understanding of altered lipid metabolism by isocitrate dehydrogenase 1 (IDH1) mutations in gliomas at a compartment-specific level is limited. Here, the authors use Raman spectroscopy to monitor organelle-specific metabolic changes and report that IDH1 mutations induce phospholipid imbalances which lead to ER and Golgi dilation.

Abstract Background Leg length discrepancy is often associated with distal femur angular deformities such as valgus or flexion. This study aims to report a new technique for simultaneous limb lengthening and acute distal femoral angular correction. Methods A retrospective chart review of patients undergoing a single procedure was conducted. Patients included had a single operation where they underwent distal femur osteotomy stabilized with a plate followed by antegrade nailing with a magnetically controlled intramedullary lengthening nail (PRECICE, Ellipse Technologies, Inc., Irvine, CA, USA) using a trochanteric entry. Results Seven femurs from 7 patients were included. The average age at operation was 13.6 years, and the leg length difference was 51 mm (range 30–105 mm). Associated deformities were valgus (4), knee flexion contracture (2), and both valgus and flexion contracture (1). Lengthening achieved was 43 mm (P = 0.0036), with a consolidation index of 27 days/cm and reliability of 0.87 (6/7). The 5 patients with angulation had an improvement of valgus from 12 to 4° (P = 0.006) and of the mechanical axis deviation from 34 to 3 mm (P = 0.0001). The range of motion also improved in the 3 patients with contractures. Preoperative gait disturbance, hip and knee pain, and functional scoliosis resolved after the limb deformities were corrected. Conclusion Combining a magnetic internal lengthening nail with a second distal osteotomy stabilized with a plate can successfully correct limb length and distal femur deformity acutely without altering the expected result of each procedure.

Some brightly colored structures are only visible when organisms are moving, such as parts of wings that are only visible in flight. For example, the primarily brown Carolina grasshopper (Dissosteira carolina) has contrasting black-and-cream hindwings that appear suddenly when it takes off, then oscillate unpredictably throughout the main flight before disappearing rapidly upon landing. However, the temporal dynamics of hindwing coloration in motion have not previously been investigated, particularly for animals that differ from humans in their temporal vision. To examine how quickly this coloration appears to a variety of non-human observers, we took high-speed videos of D. carolina flights in the field. For each of the best-quality takeoffs and landings, we performed a frame-by-frame analysis on how the relative sizes of the different-colored body parts changed over time. We found that in the first 7.6 ± 1.5 ms of takeoff, the hindwings unfurled to encompass 50% of the visible grasshopper, causing it to roughly double in size. During the main flight, the hindwings transitioned 6.4 ± 0.4 times per second between pauses and periods of active wing-beating (31.4 ± 0.5 Hz), creating an unstable, confusing image. Finally, during landings, the hindwings disappeared in 11.3 ± 3.0 ms, shrinking the grasshopper to 69 ± 9% of its main flight size. Notably, these takeoffs and landings occurred faster than most recorded species are able to sample images, which suggests that they would be near-instantaneous to a variety of different viewers. We therefore suggest that D. carolina uses its hindwings to initially startle predators (deimatic defense) and then confuse them and disrupt their search images (protean defense) before rapidly returning to crypsis.

This study assessed COVID-19 experiences among minority older adults in Houston, Texas. An electronic survey was administered to community-dwelling older adults, and the open-ended responses of 458 minority adults were analyzed using thematic analysis. Through an inductive coding approach, 2 unexpected main themes emerged regarding family: fear of COVID-19 spreading among their family and modifications to family and community interactions. These older minority adults framed their personal COVID-19 experiences through the lens of family and their community, demonstrating the importance of integrating family considerations into pandemic planning, response, and recovery efforts for minority older adults.